U.S. DEPARTMENT OF AGRICULTURE 

Marketing and Regulatory Programs

Animal and Plant Health Inspection Service

Veterinary Services 

VS Memorandum 800.125 

1 | Page

Preparation and Submission of Adverse Event Reports for Biological Products by 

Licensees and Permittees

1. Purpose and Background 

The Center for Veterinary Biologics (CVB) is issuing this memorandum to provide 

guidance to all licensees and permittees on preparing and submitting adverse event 

reports to Animal and Plant Health Inspection Service (APHIS) Veterinary Services (VS). 

This guidance ensures reports meet the intent of the regulations, as specified in the 

recently updated regulations included in title 9, Code of Federal Regulations (9 CFR), 

116.9. Adverse event reports submitted to licensees and permittees are an important 

part of CVB’s mission to ensure that veterinary biological products are in compliance with 

the Virus-Serum-Toxin Act.

The Virus-Serum-Toxin Act regulations concerning records and reports, as specified in 9 

CFR 116.9, require veterinary biologics licensees and permittees to record and submit 

reports concerning adverse events associated with the use of the veterinary biological 

products they produce and distribute. These records and reports will assist VS in 

monitoring the performance of licensed veterinary biological products over time. This 

allows VS to provide complete and accurate information to consumers regarding adverse 

events or possible concerns associated with the use of these products. Adverse event 

report records are maintained for a period of three years after the adverse event is 

received. Adverse event reports determined by the licensee or permittee to be productrelated, serious, and unexpected must also be reported immediately. All other adverse 

events must be reported within 90 calendar days of the date the report was first 

received. APHIS amended the definitions in 9 CFR 101.2 to define adverse events and 

adverse event report.

The regulations regarding adverse event reporting went into effect June 18, 2018. 

However, CVB Notice 18-09, “Implementation Period for the Submission of Adverse 

Event Reports,” posted on June 25, 2018, explains that there is an eighteen (18) month 

minimum phase-in period for the implementation of the regulations, during which CVB 

will not require licensees and permittees to submit adverse event reports as described in 

9 CFR 116.9.

Pursuant to the Congressional Review Act (5 U.S.C. § 801 et seq.), the Office of 

Information and Regulatory Affairs designated this rule as a non-major rule, as defined by 

5 U.S.C. § 804(2).

2. Document Status 

A. Issue Date: 08/17/2020. 
U.S. DEPARTMENT OF AGRICULTURE 

Marketing and Regulatory Programs

Animal and Plant Health Inspection Service

Veterinary Services 

VS Memorandum 800.125 

2 | Page

B. This is a new guidance document. 

3. Authority and References 

A. Authorities (Code of Federal Regulations (CFR)): 

• 7 CFR 371.4

• 9 CFR 101.2 

• 9 CFR 116.9 

B. References 

• CVB Notice 18-09 

C. Definitions 

1) Adverse Event: Any observation in animals, whether or not the cause of the event 

is known, that is unfavorable and unintended, and that occurs after any use (as 

indicated on the label or any off-label use) of a biological product, including 

events related to a suspected lack of expected efficacy. For products intended to 

diagnose disease, adverse events refer to a failure in product performance that 

hinders an expected discovery of the correct diagnosis. 

2) Adverse Event Report (AER): Direct communication concerning the occurrence of 

an adverse event from an identifiable firsthand reporter which includes the 

following information:

a) An identifiable reporter;

b) An identifiable animal*;

c) An identifiable biologic product; and

d) One or more adverse events.

Note: Report all AERs for VS licensed/permitted product distributed within 

domestic and/or international markets.

*Where specific information regarding an animal’s identity is not readily available, 

CVB will consider the species for which the product was used to be the minimum 

information for an “identifiable animal.”

3) Marketing Authorization Holder (MAH) The MAH is the licensee or permittee who 

is responsible for the pharmacovigilance of the licensed or permitted biological 

product.
U.S. DEPARTMENT OF AGRICULTURE 

Marketing and Regulatory Programs

Animal and Plant Health Inspection Service

Veterinary Services 

VS Memorandum 800.125 

3 | Page

4) ABON System: The ABON system is the acceptable method used for assessing 

causality and categorizes adverse events into five (5) main categories, which are 

as follows: 

Probable (A) Possible (B) Unclassifiable (O) Inconclusive (O1) and Unlikely (N).

a) Category A: Probable - All of the following minimum criteria apply: 

i. There should be a reasonable association in time between the 

administration of the biological product and onset and duration of the 

reported adverse event.

ii. The description of the clinical event should be consistent with, or at least 

plausible, given the known ingredients of the biological product described 

in the adverse event.

iii. There should be no other equally plausible explanation(s) of the case 

reported.

b) Category B: Possible - The administration and/or use of the biological product 

is another possible and plausible cause for the reported adverse event where 

the available data do not meet the criteria for inclusion in Category A.

c) Category O: Unclassifiable/Unassessable - Applied to cases where reliable data 

is unavailable or insufficient to make an assessment of causality.

d) Category O1: Inconclusive - Associative other factors prevented the assessor 

from drawing a definitive conclusion regarding causality (A or B), but in which 

association cannot be discounted.

e) Category N: Unlikely - Sufficient information exists to establish beyond a 

reasonable doubt that the adverse event described in the AER was not likely 

due to the use of the veterinary biological product.

5) Serious Adverse Event: Any adverse event which results in death, is lifethreatening, results in persistent or significant disability/incapacity, or a 

congenital anomaly or birth defect. 

6) Unexpected Adverse Event: An unexpected adverse event is an adverse event of 

which the nature, severity, or outcome is not consistent with VS-approved 

labeling for licensed or permitted products distributed within the United States or

filed Outlines of Production. 

7) Product-Related: The submitter has assessed causality to be probable or possible 

according to the ABON causality assessment classification system. For individual 

AERs, the ABON classification of probable or possible does not indicate that the 
U.S. DEPARTMENT OF AGRICULTURE 

Marketing and Regulatory Programs

Animal and Plant Health Inspection Service

Veterinary Services 

VS Memorandum 800.125 

4 | Page

MAH has established a causal link for any or all clinical signs reported with the 

adverse event. 

8) Causality Assessment: Each MAH or licensed or permitted distributor (refer to 

Section A.2 below) will make a determination as to whether the adverse event(s) 

described in an individual AER is/are related to the MAH’s biological product(s) 

identified in the AER. For the purposes of reporting adverse events to CVB under 

9 CFR 116.9, the “ABON system” is the acceptable method to use for assessing 

causality for each product the firm is responsible for reporting. 

9) Veterinary Dictionary for Drug Related Affairs (VeDDRA) Terminology: A list of 

terms for reporting clinical signs in suspected adverse events in animals and 

humans to veterinary medicinal products, of which veterinary biological products 

are included. 

 

10) Gateway: A dedicated and secure transmission portal that allows licensees and 

permittees to electronically transmit either single or batch AER cases in xml file 

format to CVB, with subsequent importation of these cases into the CVB 

pharmacovigilance databases. 

4. Audience 

VS employees, licensees and permittees.

5. Guidance 

A. MAH Responsibilities and Requirements 

1) Implement a documented process to ensure AERs are captured, thoroughly 

assessed, appropriate action taken as required, and reported to CVB in 

compliance with the regulations.

2) The MAH that holds the license or permit for the biological product identified in 

an AER is ultimately responsible for the accuracy, quality, and actions taken as a 

result of the AER submitted to CVB for the product. Third parties or distributors 

are not authorized by VS to submit AERs on behalf of the MAH unless the 

distributor is a licensee or permittee and the MAH agrees with this arrangement.

3) A primary pharmacovigilance contact must be identified for the MAH. An APHIS 

Form 2007 must be submitted to CVB with the role of Consumer Complaint 

Contact (CCC) selected. The MAH may not submit AERs to CVB or obtain guidance 

and instructions for XML file format submissions of AERs until the CCC has been 

identified by the MAH and the APHIS Form 2007 for this individual has been 

received and processed by CVB. Up to four CCCs may be identified per licensee or 

permittee.
U.S. DEPARTMENT OF AGRICULTURE 

Marketing and Regulatory Programs

Animal and Plant Health Inspection Service

Veterinary Services 

VS Memorandum 800.125 

5 | Page

B. Methods to Initiate and Submit AERs to CVB 

1) Licensees and permittees must report individual AERs to CVB using one of the two 

methods listed below to maintain compliance with 9 CFR 116.9:

a) Gateway: Transmit AERs generated in XML file format electronically through 

the Gateway. Use of the Gateway is not limited to the number of cases to be 

submitted, or the type of pharmacovigilance information gathering systems 

used, as long as CVB-supplied user guidance is followed (see Section B.2.a).

b) PV Express II: The PV Express II electronic adverse event reporting form for 

industry is located on the CVB website: 

https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/veterinarybiologics/adverse-event-reporting/ct_vb_adverse_event

2) Guidance and instructions for preparing and submitting AERs can be accessed by:

a) XML File Format Transmission: CVB epidemiologists will provide specific AER 

formatting and onboarding guidance instructions for transmitting AERs using 

the Gateway to guide the submitter in initiating these XML submissions. Firms 

using this method must contact the CVB epidemiologists to obtain specific 

user guidance. The CVB preferred method of contact is by using the following 

email address: CVB.Pharma@usda.gov

b) Web Based Transmission: Guidance and instructions for submission of AERs 

using PV Express II can be accessed at:

https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/veterinarybiologics/adverse-event-reporting/ct_vb_adverse_event

C. Preparing Adverse Event Reports for Submission to CVB 

1) AER content: The information requested for each AER follows VICH Guidelines 24 

and 42. For more information visit: 

https://www.vichsec.org/en/guidelines/pharmacovigilance/vich-gls-24-29-35-

42.html

2) Information to report to CVB: All fields identified in the guidance document for 

Gateway XML submissions and the PV Express II online form if this information is 

known.

3) VeDDRA Coding: VeDDRA coding using VeDDRA terminology for each clinical sign 

reported as part of completing an AER for submission to CVB must be performed. 

Guidance for VeDDRA coding can be found at the AER page of the CVB website

https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/veterinarybiologics/adverse-event-reporting/ct_vb_adverse_event
U.S. DEPARTMENT OF AGRICULTURE 

Marketing and Regulatory Programs

Animal and Plant Health Inspection Service

Veterinary Services 

VS Memorandum 800.125 

6 | Page

4) Find further guidance regarding preparing AER submissions in the Appendix: 

Additional Instructions for Preparing and Submitting an AER.

D. Frequency for Reporting Adverse Events to CVB 

1) The required frequency for submitting AERs to CVB is as follows:

a) Immediate reporting: Adverse events that are serious, unexpected, and 

product related must be submitted immediately to CVB and must occur within 

three (3) business days from when the submitter makes the determination 

these criteria apply. However, the total time to make an immediate 

submission to CVB must not exceed fifteen (15) business days from the date 

when the report was first received. Refer to the Appendix, item 1) for further 

information.

b) Periodic reporting: Report adverse events not requiring immediate reporting, 

as described in Section D.1.a above, to CVB within ninety (90) calendar days of 

when the submitter first receives an individual report. 

c) Follow-up adverse event reports: Submit follow-up reports to CVB within 

fifteen (15) business days of verifying the follow-up submission as complete. 

Identify follow-up submissions with the appropriate case number from the 

original submission.

E. Reporting Distribution to the Marketplace 

1) Annually provide doses/tests (for diagnostic test kit products) distributed to the 

marketplace, by country, for each biological product for the twelve (12) months 

preceding the end of each calendar year. Supply this information within sixty (60)

calendar days after the end of the calendar year. It is not necessary to provide this 

information for products that have not had any AERs reported to the licensee or 

permittee during the above referenced time period.

2) For circumstances including, but not necessarily limited to, conditional license 

requirements and other CVB-directed requests for periodic adverse event 

reporting (for example, quarterly AERs) provide the doses/tests to the 

marketplace, by country, for the time period specified in the CVB request. 

F. Implementation/Applicability 

Updated policy in this memorandum is effective six (6) months after the Issue Date 

listed in Section 2.A 
U.S. DEPARTMENT OF AGRICULTURE 

Marketing and Regulatory Programs

Animal and Plant Health Inspection Service

Veterinary Services 

VS Memorandum 800.125 

7 | Page

Appendix: Additional Instructions for Preparing and Submitting an AER

The following is not an all-inclusive listing, but rather some key items to consider when preparing 

AERs for submission to CVB:

1. For AERs submitted in accordance with 9 CFR 116.9(b)(2) and 116.9(b)(3), the original 

receipt date is the date of first receipt of information by the submitter responsible for 

reporting the AER to CVB. CVB interprets receipt of information to include the following 

four (4) data points:

a) An identifiable reporter;

b) An identifiable animal;

c) An identifiable biologic product; and

d) One or more adverse events.

2. The date remains the same for follow-up or future submissions concerning an AER. CVB 

expects each submitter to perform due diligence to obtain the four (4) data points noted 

above when initially obtaining information from the reporter.

3. Provide the correct establishment and product code number as assigned by CVB for 

each biological product that the submitter is responsible for reporting.

4. For AERs involving human exposure to a biological product, report only symptomatic 

human exposures to CVB.

5. Each report of an adverse event must provide VeDDRA terms for each of the clinical 

signs described in the case narrative. CVB will use the latest version of VeDDRA terms; 

however, CVB will also accept the previous three (3) versions of VeDDRA. Guidance for 

VeDDRA coding can be found at the AER page of the CVB website: 

https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/veterinary-biologics/adverseevent-reporting/ct_vb_adverse_event

6. Adverse event reports submitted for diagnostic test kit products should not include 

issues related to technical errors or equipment failures.

7. For VeDDRA coding of diagnostic test kit products use “unclassifiable adverse event” as 

the only VeDDRA term.

8. Do not report product defect issues to CVB as an adverse event if such issues are not 

associated with an adverse event as defined in Section C.1 above. Product defect issues 

may include, but are not limited to: Labeling errors, particulates observed in final 

containers, dented vial caps, or product color changes.

9. Consider initiating more than one (1) AER in instances where multiple animals are 

involved and multiple clinical signs reported. For example, if two (2) dogs are identified 
U.S. DEPARTMENT OF AGRICULTURE 

Marketing and Regulatory Programs

Animal and Plant Health Inspection Service

Veterinary Services 

VS Memorandum 800.125 

8 | Page

in one (1) adverse event, and one (1) has an injection site reaction while the other dog 

has lethargy and vomiting, report these as two (2) separate adverse events.

10. Do not identify or submit AERs as immediate reports under 9 CFR 116.9 or identify as 

expedited/three- (3-)day alerts in an AER submission, regardless of the actual 

submission time-frame, that do not meet the three (3) criteria of being serious, 

unexpected, and product related.

11. Each submitter should exercise due diligence to obtain and report the correct serial 

number for each biological product identified in an AER. However, CVB knows the 

primary reporter may not always provide this information. In this case, use the term 

“unknown” in place of the serial number.